Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia

• Published in: British journal of cancer Vol. 117; no. 2; pp. 256 - 265
• Main Authors: Forero-Castro, Maribel, Robledo, Cristina, Benito, Rocío, Bodega-Mayor, Irene, Rapado, Inmaculada, Hernández-Sánchez, María, Abáigar, María, Maria Hernández-Sánchez, Jesús, Quijada-Álamo, Miguel, María Sánchez-Pina, José, Sala-Valdés, Mónica, Araujo-Silva, Fernanda, Kohlmann, Alexander, Luis Fuster, José, Arefi, Maryam, de las Heras, Natalia, Riesco, Susana, Rodríguez, Juan N, Hermosín, Lourdes, Ribera, Jordi, Camos Guijosa, Mireia, Ramírez, Manuel, de Heredia Rubio, Cristina Díaz, Barragán, Eva, Martínez, Joaquín, Ribera, José M, Fernández-Ruiz, Elena, Hernández-Rivas, Jesús-María
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.07.2017; Nature Publishing Group
• Subjects: 692/53/2422; 692/699/67/1990/283; Acute lymphoblastic leukemia; Adolescent; Adult; Adults; Aged; Aged, 80 and over; B-Lymphocytes - pathology; Bioindicators; Biomarkers; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Child; Child, Preschool; Children; Disease-Free Survival; Drug Resistance; Epidemiology; Female; Gene Expression Regulation, Neoplastic; Genetics & Genomics; genetics-and-genomics; High-Throughput Nucleotide Sequencing; Humans; Infant; Interleukin 7 receptors; Janus kinase 2; Janus Kinase 2 - genetics; Leukemia; Lymphocytes B; Male; Medical prognosis; Middle Aged; Molecular Medicine; Mutation; Oncology; p53 Protein; Pax5 protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Prognosis; Receptors, Cytokine - biosynthesis; Risk factors; Runx1 protein; Survival; Treatment Outcome; Tumor Suppressor Protein p53 - genetics; mutation; acute lymphoblastic leukaemia (ALL); prognosis; next-generation sequencing (NGS); outcome; survival
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2017.152

Background: In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols. Methods: Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR). Results: A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P =0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 ( P =0.047) or BCR-ABL1 fusions ( P <0.0001). In children, TP53 mut was associated with lower OS (5-year OS: 50% vs 86%, P =0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P =0.009) and higher RR (5-year RR: 33.3% vs 18.6% P =0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P =0.04). In adults, TP53 mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P =0.019) and a higher RR (5-year RR: 100% vs 61.4%, P =0.029), whereas JAK2 mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P =0.035) and a higher RR (5-year RR: 100% vs 60.4%, P =0.002). TP53 mut was an independent risk factor for shorter OS (HR=2.3; P =0.035) and, together with JAK2 mut, also were independent markers of poor prognosis for RR ( TP53 mut: HR=5.9; P =0.027 and JAK2 mut: HR=5.6; P =0.036). Conclusions: TP53 mut and JAK2 mut are potential biomarkers associated with poor prognosis in B-ALL patients.